These studies are designed to increase our understanding of the neurochemical mechanisms that are relevant to cocaine and opioid abuse. The elucidation of these processes is critical for the development of effective treatment strategies. Cocaine and opioids such as morphine and heroin are widely abused substances that activate dopamine-rich regions of the brain, and there are many studies suggesting that there are interactions between the actions of psychomotor stimulants and opioids. The specific objective of this project is to examine what role opioid receptors might play in the development tolerance and sensitization to cocaine and to further investigate the manner by which cocaine may interact with opioid receptors. Chronic continuous administration of cocaine produces large increases in locomotor activity, to which rats become partially tolerant over the course of several days. In contrast to this, continuous administration of morphine produces moderate increases in locomotor activity which remain constant over the course of a week. When the two drugs are coadministered, they produce levels of activity greater than with either drug alone, and the tolerance that is observed to cocaine appears to be less pronounced. Studies examining the mechanism by which this effect occurs are currently underway. Chronic treatment with an opioid receptor antagonist produces an increase in the number of mu opioid receptors (sites where opioid compounds act) in the brain. There are also increases in the function of opioid receptors following chronic antagonist administration, as evidenced by an increase in receptor regulation of second messenger function in vitro, and of opioid analgesia in vivo. These receptors are also increased in specific brain regions following chronic, continuous cocaine administration. Treatment with an opioid agonist, such as morphine produces a down-regulation (decrease) of :-opioid receptors, and tolerance to opioid analgesia. When cocaine and morphine are chronically coadministered, there is a loss of the tolerance normally associated with chronic morphine treatment. These findings, taken together with the in vitro receptor and functional assays, suggest that the effects of chronic cocaine on :-opioid receptors are similar to those seen following chronic opioid antagonist treatment. Since cocaine does not bind to opioid receptors, this effect is likely to be via an indirect action (eg. release of an agent that binds to opioid receptors or a heterologous regulation of receptors regulating common transduction systems). Further studies are aimed at elucidating the mechanism by which cocaine produces these effects. These findings suggest that the opioid system may play an important role in the behavioral effects produced by cocaine and may serve as a target for the development of medical therapies for cocaine abuse.